tbuckley/cabot-search huggingface dataset:
Antibiotic Prophylaxis in Infants with Grade III, IV, or V Vesicoureteral Reflux
Authors: William Morello, Esra Baskin, Augustina Jankauskiene, Fatos Yalcinkaya, Aleksandra Zurowska, Giuseppe Puccio, Jessica Serafinelli, Angela La Manna, Grażyna Krzemień, Marco Pennesi, Claudio La Scola, Francesca Becherucci, Milena Brugnara, Selcuk Yuksel, Djalila Mekahli, Roberto Chimenz, Diego De Palma, Pietro Zucchetta, Donatas Vajauskas, Dorota Drozdz, Maria Szczepanska, Salim Caliskan, Jacques Lombet, Dario G. Minoli, Stefano Guarino, Kaan Gulleroglu, Dovile Ruzgiene, Agnieszka Szmigielska, Egidio Barbi, Zeynep B. Ozcakar, Anna Kranz, Andrea Pasini, Marco Materassi, Stephanie De Rechter, Gema Ariceta, Lutz T. Weber, Pierluigi Marzuillo, Irene Alberici, Katarzyna Taranta-Janusz, Alberto Caldas Afonso, Marcin Tkaczyk, Margarita Català, Jose E. Cabrera Sevilla, Otto Mehls, Franz Schaefer, Giovanni Montini
Journal: New England Journal of Medicine (2023)

The efficacy of continuous antibiotic prophylaxis in preventing urinary tract infection (UTI) in infants with grade III, IV, or V vesicoureteral reflux is controversial. Download a PDF of the Research Summary. In this investigator-initiated, randomized, open-label trial performed in 39 European centers, we randomly assigned infants 1 to 5 months of age with grade III, IV, or V vesicoureteral reflux and no previous UTIs to receive continuous antibiotic prophylaxis (prophylaxis group) or no treatment (untreated group) for 24 months. The primary outcome was the occurrence of the first UTI during the trial period. Secondary outcomes included new kidney scarring and the estimated glomerular filtration rate (GFR) at 24 months. A total of 292 participants underwent randomization (146 per group). Approximately 75% of the participants were male; the median age was 3 months, and 235 participants (80.5%) had grade IV or V vesicoureteral reflux. In the intention-to-treat analysis, a first UTI occurred in 31 participants (21.2%) in the prophylaxis group and in 52 participants (35.6%) in the untreated group (hazard ratio, 0.55; 95% confidence interval [CI], 0.35 to 0.86; P=0.008); the number needed to treat for 2 years to prevent one UTI was 7 children (95% CI, 4 to 29). Among untreated participants, 64.4% had no UTI during the trial. The incidence of new kidney scars and the estimated GFR at 24 months did not differ substantially between the two groups. Pseudomonas species, other non–Escherichia coli organisms, and antibiotic resistance were more common in UTI isolates obtained from participants in the prophylaxis group than in isolates obtained from those in the untreated group. Serious adverse events were similar in the two groups. In infants with grade III, IV, or V vesicoureteral reflux and no previous UTIs, continuous antibiotic prophylaxis provided a small but significant benefit in preventing a first UTI despite an increased occurrence of non–E. coli organisms and antibiotic resistance. (Funded by the Italian Ministry of Health and others; PREDICT ClinicalTrials.gov number, NCT02021006; EudraCT number, 2013-000309-21.) QUICK TAKE VIDEO SUMMARYAntibiotic Prophylaxis in Infants with Vesicoureteral Reflux 02:09
A Doctrine in Name Only — Strengthening Prohibitions against the Corporate Practice of Medicine
Authors: Jane M. Zhu, Hayden Rooke-Ley, Erin Fuse Brown
Journal: New England Journal of Medicine (2023)

Interview with Erin Fuse Brown on the role of corporate-practice-of-medicine laws in a changing health care environment. (06:57)Download Rapid corporatization of health care raises questions about the corporate-practice-of-medicine doctrine and whether state laws could be strengthened to protect the profession and the public interest.
Case 28-2023: A 37-Year-Old Man with a Rash
Authors: Frank M. Volpicelli, Robert H. Goldstein, E. Zachary Nussbaum
Journal: New England Journal of Medicine (2023)

A 37-year-old man was admitted because of difficulty with swallowing and a diffuse maculopapular rash. Laboratory evaluation revealed lymphopenia and an elevated globulin gap. A diagnosis was made.
Actuated tissue engineered muscle grafts restore functional mobility after volumetric muscle loss
Authors: Erin Rousseau, Ritu Raman, Tigist Tamir, Angel Bu, Shriya Srinivasan, Naomi Lynch, Robert Langer, Forest M. White, Michael J. Cima
Journal: Biomaterials (2023)

Damage that affects large volumes of skeletal muscle tissue can severely impact health, mobility, and quality-of-life. Efforts to restore muscle function by implanting tissue engineered muscle grafts at the site of damage have demonstrated limited restoration of force production. Various forms of mechanical and biochemical stimulation have been shown to have a potentially beneficial impact on graft maturation, vascularization, and innervation. However, these approaches yield unpredictable and incomplete recovery of functional mobility. Here we show that targeted actuation of implanted grafts, via non-invasive transcutaneous light stimulation of optogenetic engineered muscle, restores motor function to levels similar to healthy mice 2 weeks post-injury. Furthermore, we conduct phosphoproteomic analysis of actuated engineered muscle in vivo and in vitro to show that repeated muscle contraction alters signaling pathways that play key roles in skeletal muscle contractility, adaptation to injury, neurite growth, neuromuscular synapse formation, angiogenesis, and cytoskeletal remodeling. Our study uncovers changes in phosphorylation of several proteins previously unreported in the context of muscle contraction, revealing promising mechanisms for leveraging actuated muscle grafts to restore mobility after volumetric muscle loss.
Acute myeloid leukemia with mutated <i>TP53</i>: Is this newly proposed entity oversimplifying a complex group of neoplasms?
Authors: Hong Fang, L. Jeffery Medeiros, Wei Wang
Journal: American Journal of Hematology (2023)

Acute myeloid leukemia with mutated TP53: Is this newly proposed entity oversimplifying a complex group of neoplasms?To the Editor, In the recently published International Consensus Classification (ICC) and the fifth edition of the World Health Organization classification on myeloid neoplasms, 1,2 the importance of TP53 mutation in disease pathogenesis and prognosis is recognized.The ICC goes a step further in recognizing acute myeloid leukemia (AML) with mutated TP53 as a
Real-time surveillance of international SARS-CoV-2 prevalence using systematic traveller arrival screening: An observational study
Authors: Adam J. Kucharski, Kiyojiken Chung, Maite Aubry, Iotefa Teiti, Anita Teissier, Vaea Richard, Timothy W. Russell, Raphaëlle Bos, Sophie Olivier, Van-Mai Cao-Lormeau
Journal: PLoS Medicine (2023)

Effective Coronavirus Disease 2019 (COVID-19) response relies on good knowledge of population infection dynamics, but owing to under-ascertainment and delays in symptom-based reporting, obtaining reliable infection data has typically required large dedicated local population studies. Although many countries implemented Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) testing among travellers, it remains unclear how accurately arrival testing data can capture international patterns of infection, because those arrival testing data were rarely reported systematically, and predeparture testing was often in place as well, leading to nonrepresentative infection status among arrivals.In French Polynesia, testing data were reported systematically with enforced predeparture testing type and timing, making it possible to adjust for nonrepresentative infection status among arrivals. Combining statistical models of polymerase chain reaction (PCR) positivity with data on international travel protocols, we reconstructed estimates of prevalence at departure using only testing data from arrivals. We then applied this estimation approach to the United States of America and France, using data from over 220,000 tests from travellers arriving into French Polynesia between July 2020 and March 2022. We estimated a peak infection prevalence at departure of 2.1% (95% credible interval: 1.7, 2.6%) in France and 1% (95% CrI: 0.63, 1.4%) in the USA in late 2020/early 2021, with prevalence of 4.6% (95% CrI: 3.9, 5.2%) and 4.3% (95% CrI: 3.6, 5%), respectively, estimated for the Omicron BA.1 waves in early 2022. We found that our infection estimates were a leading indicator of later reported case dynamics, as well as being consistent with subsequent observed changes in seroprevalence over time. We did not have linked data on traveller demography or unbiased domestic infection estimates (e.g., from random community infection surveys) in the USA and France. However, our methodology would allow for the incorporation of prior data from additional sources if available in future.As well as elucidating previously unmeasured infection dynamics in these countries, our analysis provides a proof-of-concept for scalable and accurate leading indicator of global infections during future pandemics.
Prognostic Factors for Relapse in Patients With Clinical Stage I Testicular Seminoma: A Nationwide, Population-Based Cohort Study
Authors: Thomas Wagner, Birgitte Grønkær Toft, Jakob Lauritsen, Mikkel Bandak, Ib Jarle Christensen, Birte Engvad, Michael Kreiberg, Mads Agerbæk, Lars Dysager, Josephine Julie Rosenvilde, Daniel Berney, Gedske Daugaard
Journal: Journal of Clinical Oncology (2023)

Approximately 20% of patients with clinical stage I seminoma relapse. Tumor size and rete testis invasion have been identified as risk factors for relapse. However, the level of evidence supporting the use of these risk factors in clinical decision making is low. Previous studies have been hampered by selection bias and variable pathology reporting that limit interpretation and generalization of results. We assessed prognostic factors for relapse in an unselected nationwide population-based setting with centralized pathology review.Patients with clinical stage I seminoma diagnosed from January 2013 to December 2018 were identified in the prospective Danish Testicular Cancer database. By linkage to the Danish National Pathology Registry, histologic slides from the orchiectomy specimens were retrieved and reviewed blinded to the clinical outcome. Clinical data were obtained from medical records with follow-up until July 2022. The association between prespecified potential clinical and histopathologic prognostic factors and relapse was assessed by the use of Cox regression analysis.Of 924 patients included, 148 (16%) patients relapsed during a median follow-up of 6.3 years. Invasion of the testicular hilum (rete testis and hilar soft tissue), lymphovascular invasion, and elevated preorchiectomy levels of β-human chorionic gonadotropin and lactate dehydrogenase were independent predictors of relapse. The estimated 5-year risk of relapse ranged from 6% in patients with no risk factors to 62% in patients with all four risk factors with tumor extension into the hilar soft tissue of the testicular hilum. After internal model validation, the prognostic model had an overall concordance statistic of 0.70.The provided prognostic factors could replace current risk factors in guidelines and be used in future studies investigating risk-adapted follow-up and treatment strategies.
The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis
Authors: Yanning Xu, Arash Derakhshan, Ola Hysaj, Lea Wildisen, Till Ittermann, Alessandro Pingitore, Nazanin Abolhassani, Marco Medici, Lambertus A L M Kiemeney, Niels P Riksen, Robin P F Dullaart, Stella Trompet, Marcus Dörr, Suzanne J Brown, Börge Schmidt, Dagmar Führer-Sakel, Mark P J Vanderpump, Axel Muendlein, Heinz Drexel, Howard A Fink, M Kamran Ikram, Maryam Kavousi, Connie M Rhee, Isabela M Bensenor, Fereidoun Azizi, Graeme J Hankey, Massimo Iacoviello, Misa Imaizumi, Graziano Ceresini, Luigi Ferrucci, José A Sgarbi, Douglas C Bauer, Nick Wareham, Kristien Boelaert, Stephan J L Bakker, J Wouter Jukema, Bert Vaes, Giorgio Iervasi, Bu B Yeap, Rudi G J Westendorp, Tim I M Korevaar, Henry Völzke, Salman Razvi, Jacobijn Gussekloo, John P Walsh, Anne R Cappola, Nicolas Rodondi, Robin P Peeters, Layal Chaker
Journal: The Lancet Diabetes & Endocrinology (2023)
Alternative splicing of its 5′-UTR limits CD20 mRNA translation and enables resistance to CD20-directed immunotherapies
Authors: Zhiwei Ang, Luca Paruzzo, Katharina E. Hayer, Carolin Schmidt, Manuel Torres Diz, Feng Xu, Urvi Zankharia, Yunlin Zhang, Samantha Soldan, Sisi Zheng, Catherine D. Falkenstein, Joseph P. Loftus, Scarlett Y. Yang, Mukta Asnani, Patricia King Sainos, Vinodh Pillai, Emeline Chong, Marilyn M. Li, Sarah K. Tasian, Yoseph Barash, Paul M. Lieberman, Marco Ruella, Stephen J. Schuster, Andrei Thomas-Tikhonenko
Journal: Blood (2023)

Aberrant skipping of coding exons in CD19 and CD22 compromises the response to immunotherapy in B-cell malignancies. Here, we showed that the MS4A1 gene encoding human CD20 also produces several messenger RNA (mRNA) isoforms with distinct 5' untranslated regions. Four variants (V1-4) were detected using RNA sequencing (RNA-seq) at distinct stages of normal B-cell differentiation and B-lymphoid malignancies, with V1 and V3 being the most abundant. During B-cell activation and Epstein-Barr virus infection, redirection of splicing from V1 to V3 coincided with increased CD20 positivity. Similarly, in diffuse large B-cell lymphoma, only V3, but not V1, correlated with CD20 protein levels, suggesting that V1 might be translation-deficient. Indeed, the longer V1 isoform contained upstream open reading frames and a stem-loop structure, which cooperatively inhibited polysome recruitment. By modulating CD20 isoforms with splice-switching morpholino oligomers, we enhanced CD20 expression and anti-CD20 antibody rituximab-mediated cytotoxicity in a panel of B-cell lines. Furthermore, reconstitution of CD20-knockout cells with V3 mRNA led to the recovery of CD20 positivity, whereas V1-reconstituted cells had undetectable levels of CD20 protein. Surprisingly, in vitro CD20-directed chimeric antigen receptor T cells were able to kill both V3- and V1-expressing cells, but the bispecific T-cell engager mosunetuzumab was only effective against V3-expressing cells. To determine whether CD20 splicing is involved in immunotherapy resistance, we performed RNA-seq on 4 postmosunetuzumab follicular lymphoma relapses and discovered that in 2 of them, the downregulation of CD20 was accompanied by a V3-to-V1 shift. Thus, splicing-mediated mechanisms of epitope loss extend to CD20-directed immunotherapies.
Conventional versus hypofractionated postmastectomy proton radiotherapy in the USA (MC1631): a randomised phase 2 trial
Authors: Robert W Mutter, Sharmila Giri, Briant F Fruth, Nicholas B Remmes, Judy C Boughey, Christin A Harless, Kathryn J Ruddy, Lisa A McGee, Arslan Afzal, Robert W Gao, Dean A Shumway, Tamara Z Vern-Gross, Hector R Villarraga, Stephanie L Kenison, Yixiu Kang, William W Wong, Bradley J Stish, Kenneth W Merrell, Elizabeth S Yan, Sean S Park, Kimberly S Corbin, Carlos E Vargas
Journal: The Lancet Oncology (2023)
Targeting the RNA-Binding Protein HuR in Cancer
Authors: Jennifer M. Finan, Thomas L. Sutton, Dan A. Dixon, Jonathan R. Brody
Journal: Cancer Research (2023)

Abstract The RNA-binding protein human antigen R (HuR) is a well-established regulator of gene expression at the posttranscriptional level. Its dysregulation has been implicated in various human diseases, particularly cancer. In cancer, HuR is considered “active” when it shows increased subcellular localization in the cytoplasm, in addition to its normal nuclear localization. Cytoplasmic HuR plays a crucial role in stabilizing and enhancing the translation of prosurvival mRNAs that are involved in stress responses relevant to cancer progression, such as hypoxia, radiotherapy, and chemotherapy. In general, due to HuR's abundance and function in cancer cells compared with normal cells, it is an appealing target for oncology research. Exploiting the principles underlying HuR's role in tumorigenesis and resistance to stressors, targeting HuR has the potential for synergy with existing and novel oncologic therapies. This review aims to explore HuR's role in homeostasis and cancer pathophysiology, as well as current targeting strategies, which include silencing HuR expression, preventing its translocation and dimerization from the nucleus to the cytoplasm, and inhibiting mRNA binding. Furthermore, this review will discuss recent studies investigating the potential synergy between HuR inhibition and traditional chemotherapeutics.
Evolving therapies, neurocognitive outcomes, and functional independence in adult survivors of childhood glioma
Authors: Chiara Papini, Sedigheh Mirzaei S., Mengqi Xing, Ingrid Tonning Olsson, Peter M K de Blank, Katharine R Lange, Ralph Salloum, Deokumar Srivastava, Wendy M Leisenring, Rebecca M Howell, Kevin C Oeffinger, Leslie L Robison, Gregory T Armstrong, Kevin R Krull, Tara M Brinkman
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Treatment of childhood glioma has evolved to reduce radiotherapy exposure with the goal of limiting late toxicity. However, the associations between treatment changes and neurocognition, and the contribution of neurocognition and chronic health conditions to attainment of adult independence, remain unknown. Methods Adult survivors of childhood glioma diagnosed in 1970-1999 in the Childhood Cancer Survivor Study (n = 1284; median [minimum-maximum] 30 [18-51] years of age at assessment; 22 [15-34] years from diagnosis) self-reported neurocognitive impairment and chronic health conditions. Multivariable models evaluated associations between changes in treatment exposures (surgery only, chemotherapy [with or without surgery], cranial radiation [with or without chemotherapy and/or surgery]), and neurocognitive impairment. Latent class analysis with 5 indicators (employment, independent living, assistance with routine and/or personal care needs, driver’s license, marital or partner status) identified classes of functional independence. Path analysis tested associations among treatment exposures, neurocognitive impairment, chronic health conditions, and functional independence. Statistical tests were 2-sided. Results Cranial radiation exposure decreased over time (51%, 1970s; 46%, 1980s; 27%, 1990s]. However, compared with siblings, survivors with any treatment exposure were at elevated risk for neurocognitive impairment, including surgery only (eg, memory: relative risk = 2.22; task efficiency: relative risk = 1.88; both P &amp;lt; .001). Three classes of functional independence were identified: independent (58%), moderately independent (20%), and nonindependent (22%). Cranial radiation was associated with nonindependence through impaired task efficiency (β = 0.06), sensorimotor (β = 0.06), and endocrine (β = 0.10) chronic health conditions and through the associations between these conditions and task efficiency (each β = 0.04). Sensorimotor and endocrine chronic health conditions were associated with nonindependence through memory. Conclusion Most long-term glioma survivors achieve adult independence. However, functional nonindependence is associated with treatment-related neurocognitive impairment and chronic health conditions.
<i>BARD1</i> germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma
Authors: Michael P Randall, Laura E Egolf, Zalman Vaksman, Minu Samanta, Matthew Tsang, David Groff, J Perry Evans, Jo Lynne Rokita, Mehdi Layeghifard, Adam Shlien, John M Maris, Sharon J Diskin, Kristopher R Bosse
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background High-risk neuroblastoma is a complex genetic disease that is lethal in more than 50% of patients despite intense multimodal therapy. Through genome-wide association studies (GWAS) and next-generation sequencing, we have identified common single nucleotide polymorphisms and rare, pathogenic or likely pathogenic germline loss-of-function variants in BARD1 enriched in neuroblastoma patients. The functional implications of these findings remain poorly understood. Methods We correlated BARD1 genotype with expression in normal tissues and neuroblastomas, along with the burden of DNA damage in tumors. To validate the functional consequences of germline pathogenic or likely pathogenic BARD1 variants, we used CRISPR-Cas9 to generate isogenic neuroblastoma (IMR-5) and control (RPE1) cellular models harboring heterozygous BARD1 loss-of-function variants (R112*, R150*, E287fs, and Q564*) and quantified genomic instability in these cells via next-generation sequencing and with functional assays measuring the efficiency of DNA repair. Results Both common and rare neuroblastoma-associated BARD1 germline variants were associated with lower levels of BARD1 mRNA and an increased burden of DNA damage. Using isogenic heterozygous BARD1 loss-of-function variant cellular models, we functionally validated this association with inefficient DNA repair. BARD1 loss-of-function variant isogenic cells exhibited reduced efficiency in repairing Cas9-induced DNA damage, ineffective RAD51 focus formation at DNA double-strand break sites, and enhanced sensitivity to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibition both in vitro and in vivo. Conclusions Taken together, we demonstrate that germline BARD1 variants disrupt DNA repair fidelity. This is a fundamental molecular mechanism contributing to neuroblastoma initiation that may have important therapeutic implications.
Changes in cancer-related mortality during the COVID-19 pandemic in the United States
Authors: Ugo Fedeli, Claudio Barbiellini Amidei, Xuesong Han, Ahmedin Jemal
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Few studies have examined cancer-related mortality overall, never mind select cancer types, during the COVID-19 pandemic. Data on cancer-related mortality (any mention in death certificates, multiple causes of death approach) was extracted from the US Centers for Disease Control and Prevention WONDER database. Changes in trends for age-standardized mortality rates through 1999-2021 were assessed by Joinpoint analysis. In total, 1 379 643 cancer-related deaths were registered in 2020-2021, with cancer selected as the underlying cause in 88%. After 2 decades of decline, age-standardized cancer-related mortality increased from 2019 to 2021 for all cancers (annual percentage change = 1.6%, 95% confidence interval = 0.6% to 2.6%), especially for prostate cancer (annual percentage change = 5.1%, 95% confidence interval = 2.2% to 8.2%) and hematologic cancers (annual percentage change = 4.8%, 95% confidence interval = 3.1% to 6.6%). Sharp peaks in cancer-related deaths for many cancer sites were observed during pandemic waves in both 2020 and 2021, mostly attributed to COVID-19 as the underlying cause. Multiple causes of death analyses are warranted to fully assess the impact of the pandemic on cancer-related mortality.